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EPIGENETIC S
or nearly a century after the term “epigenetics” indicators already have some level of evidence
F first surfaced on the printed page, researchers,
physicians, and others poked around in the dark
linking them with epigenetic mechanisms, includ-
ing cancers of almost all types, cognitive dysfunc-
crevices of the gene, trying to untangle the clues tion, and respiratory, cardiovascular, reproductive,
that suggested gene function could be altered by autoimmune, and neurobehavioral illnesses. Known
Matt Ray/EHP
more than just changes in sequence. Today, a wide or suspected drivers behind epigenetic processes
variety of illnesses, behaviors, and other health include many agents, including heavy metals,
M C G
G C M
A T
RNA pol II
M C G
Methyltranferases attach T A
methyl groups to DNA
G C M
A T
M C G
NH2
RNA pol II
C
CH3
N C
Protein complexes, recruited to
methylated DNA, remove acetyl
groups and repress transcription
C C
O N
Multiple Mechanisms rise much in years to come, writes a team hydralazine cause lupus in some people,
The word “epigenetic” literally means “in including Ian Morison, a senior research and demonstrated that lupus-like disease in
addition to changes in genetic sequence.” fellow in the Cancer Genetics Laboratory mice exposed to these drugs is linked with
The term has evolved to include any at New Zealand’s University of Otago, in DNA methylation alterations and interrup-
process that alters gene activity without the August 2005 Trends in Genetics. Others tion of signaling pathways similar to those
changing the DNA sequence, and leads to in the field disagree. Randy Jirtle, a profes- in people.
modifications that can be transmitted to sor of radiation oncology at Duke Univ-
daughter cells (although experiments show ersity Medical Center, and his colleagues Substantial Changes
that some epigenetic changes can be estimated in the June 2005 issue of Most epigenetic modification, by whatev-
reversed). There likely will continue to be Genome Research that there could be about er mechanism, is believed to be erased
debate over exactly what the term means 600 imprinted genes in mice; in an with each new generation, during gameto-
and what it covers. October 2005 interview Jirtle said he’s genesis and after fertilization. However,
Many types of epigenetic processes have anticipating a similar tally for humans, one of the more startling reports published
been identified—they include methylation, even though the known imprintable genes in 2005 challenges this belief and suggests
acetylation, phosphorylation, ubiquityla- of mice and people have an overlap of only that epigenetic changes may endure in at
tion, and sumolyation. Other epigenetic about 35%. least four subsequent generations of
mechanisms and considerations are likely organisms.
to surface as work proceeds. Epigenetic Links to Disease Michael Skinner, a professor of molecu-
processes are natural and essential to many Among all the epigenetics research con- lar biosciences and director of the Center
organism functions, but if they occur ducted so far, the most extensively studied for Reproductive Biology at Washington
improperly, there can be major adverse disease is cancer, and the evidence linking State University, and his team described in
health and behavioral effects. epigenetic processes with cancer is becom- the 3 June 2005 issue of Science how they
Perhaps the best known epigenetic ing “extremely compelling,” says Peter briefly exposed pregnant rats to individual
process, in part because it has been easiest to Jones, director of the University of South- relatively high levels of the insecticide
study with existing technology, is DNA ern California’s Norris Comprehensive methoxychlor and the fungicide vinclo-
methylation. This is the addition or removal Cancer Center. Halfway around the zolin, and documented effects such as
of a methyl group (CH3), predominantly world, Toshikazu Ushijima is of the same decreased sperm production and increased
where cytosine bases occur consecutively. mind. The chief of the Carcinogenesis male infertility in the male pups. Digging
DNA methylation was first confirmed to Division of Japan’s National Cancer for more information, they found altered
occur in human cancer in 1983, and has Center Research Institute says epigenetic DNA methylation of two genes. As they
since been observed in many other illnesses mechanisms are one of the five most continued the experiment, they discovered
and health conditions. important considerations in the cancer the adverse effects lasted in about 90% of
Another significant epigenetic process field, and they account for one-third to the males in all four subsequent genera-
is chromatin modification. Chromatin is one-half of known genetic alterations. tions they followed, with no additional pes-
the complex of proteins (histones) and Many other health issues have drawn ticide exposures.
DNA that is tightly bundled to fit into the attention. Epigenetic immune system The findings are not known to have
nucleus. The complex can be modified by effects occur, and can be reversed, according to been reproduced. If they are reproducible,
substances such as acetyl groups (the research published in the November– however, it could “provide a new paradigm
process called acetylation), enzymes, and December 2005 issue of the Journal of for disease etiology and basic mechanisms
some forms of RNA such as microRNAs Proteome Research by Nilamadhab Mishra, in toxicology and evolution not previously
and small interfering RNAs. This modifica- an assistant professor of rheumatology at appreciated,” says Skinner. He and his col-
tion alters chromatin structure to influence the Wake Forest University School of Med- leagues are conducting follow-up studies,
gene expression. In general, tightly folded icine, and his colleagues. The team says it’s assessing many other genes and looking at
chromatin tends to be shut down, or not the first to establish a specific link between other effects such as breast and skin
expressed, while more open chromatin is aberrant histone modification and mecha- tumors, kidney degeneration, and blood
functional, or expressed. nisms underlying lupus-like symptoms in defects.
One effect of such processes is imprint- mice, and they confirmed that a drug in Other studies have found that epigenet-
ing. In genetics, imprinting describes the the research stage, trichostatin A, could ic effects occur not just in the womb, but
condition where one of the two alleles of a reverse the modifications. The drug over the full course of a human life span.
typical gene pair is silenced by an epigenet- appears to reset the aberrant histone modi- Manel Esteller, director of the Cancer
ic process such as methylation or acetyla- fication by correcting hypoacetylation at Epigenetics Laboratory at the Spanish
tion. This becomes a problem if the two histone sites. National Cancer Center in Madrid, and his
expressed allele is damaged or contains a Lupus has also been a focus of Bruce colleagues evaluated 40 pairs of identical
variant that increases the organism’s vulner- Richardson, chief of the Rheumatology twins, ranging in age from 3 to 74, and
ability to microbes, toxic agents, or other Section at the Ann Arbor Veterans Affairs found a striking trend, described in the
harmful substances. Imprinting was first Medical Center and a professor at the 26 July 2005 issue of Proceedings of the
identified in 1910 in corn, and first con- University of Michigan Medical School. In National Academy of Sciences. Younger twin
firmed in mammals in 1991. studies published in the May–August 2004 pairs and those who shared similar lifestyles
Researchers have identified about 80 issue of International Reviews of Im- and spent more years together had very
human genes that can be imprinted, munolog y and the October 2003 issue similar DNA methylation and histone
although that number is subject to debate of Clinical Immunology, he noted that acetylation patterns. But older twins, espe-
since the strength of the evidence varies. pharmaceuticals such as the heart drug pro- cially those who had different lifestyles
That approximate number isn’t likely to cainamide and the antihypertensive agent and had spent fewer years of their lives
together, had much different patterns in The methylation changes furthermore pups could negate the benefits of high-
many different tissues, such as lymphocytes, appeared to protect the mouse offspring quality maternal care received when they
epithelial mouth cells, intra-abdominal fat, against obesity in adulthood, although were younger.
and selected muscles. there are hints that genistein may also Along with behavior, mental health
As one example, the researchers found cause health problems, via additive or syn- may be affected by epigenetic changes, says
four times as many differentially expressed ergistic effects on DNA methylation, when Arturas Petronis, head of the Krembil
genes between a pair of 50-year-old twins it interacts with other substances such as Family Epigenetics Laboratory at the
compared to 3-year-old twins, and the 50- folic acid. Centre for Addiction and Mental Health in
year-old twin with more DNA hypo- Toronto. His lab is among the first in the
methylation and histone hyperacetylation Other Drivers of Change world, and still one of only a few, to study
(the epigenetic changes usually associated Substances aren’t the only sources of epi- links between epigenetics and psychiatry.
with transcriptional activity) had the high- genetic changes. The licking, grooming, He and his colleagues are conducting large-
er number of overexpressed genes. The and nursing methods that mother rats use scale studies investigating links between
degree of epigenetic change therefore was with their pups can affect the long-term schizophrenia and aberrant methylation,
and he says understanding epigenetic
mechanisms is one of the highest priorities
in human disease biology research. “We
really need some radical revision of key
principles of the traditional genetic
research program,” he says. “Epigenetics
brings a new perspective on the old prob-
lem and new analytical tools that will help
to test the epigenetic theory.” He suggests
that more emphasis is needed on studying
non-Mendelian processes in diseases such
as schizophrenia, asthma, multiple sclero-
sis, and diabetes.
The past decade has also been produc-
tive in developing strong links between
aberrant DNA methylation and aging, says
Jean-Pierre Issa, a professor of medicine at
The University of Texas M.D. Anderson
Cancer Center. He presented information
on aging and epigenetic effects at a
November 2005 conference titled “Envi-
ronmental Epigenomics, Imprinting, and
Disease Susceptibility,” held in Durham,
North Carolina, and sponsored in part by
the NIEHS. Some of the strongest, decade-
A pup of a different color. Supplementation of maternal diet with genistein and other compounds old evidence shows progressive increases in
induced alterations in DNA methylation that were reflected in offspring coat color changes. DNA methylation in aging colon tissues,
and more recent evidence links hyperme-
thylation with atherosclerosis. Altered, age-
directly linked with the degree of change behavior of their offspring, and those related methylation has also been found in
in genetic function. results can be tied to changes in DNA tissues in the stomach, esophagus, liver,
Sometimes the effects of epigenetic methylation and histone acetylation at a kidney, and bladder, as well as the tissue
mechanisms show up in living color. glucocorticoid receptor gene promoter in types studied by Esteller. Much of Issa’s
Changes in the pigmentation of mouse the pup’s hippocampus. This finding was current work focuses on the links between
pup fur, ranging from yellow to brown, published in the August 2004 issue of epigenetic processes, aging, the environ-
were directly tied to supplementation of Nature Neuroscience by Moshe Szyf, a pro- ment, and cancer, and possible ways to
the pregnant mother’s diet with vitamin fessor in McGill University’s Department therapeutically reverse methylation linked
B 12, folic acid, choline, and betaine, of Pharmacology and Therapeutics, and with cancer.
according to studies by Jirtle and Robert his colleagues. In the same study, the
Waterland published in August 2003 (issue researchers found that the effects weren’t Current and Future Quandaries
15) in Molecular and Cellular Biology. The written in stone; giving the drug tricho- The accumulated evidence indicates that
color changes were directly linked to alter- statin A to older pups could help reverse many genes, diseases, and environmental
ations in DNA methylation. In a study the effects of poor maternal care received substances are part of the epigenetics pic-
forthcoming in the April 2006 issue of when they were younger. In the 6 June ture. However, the evidence is still far too
EHP, Jirtle and his colleagues also induced 2003 Journal of Biological Chemistry and thin to form a basis for any overarching
these alterations through maternal inges- the 23 November 2005 Journal of theories about which substances and
tion of genistein, the major phytoestrogen Neuroscience, Szyf and many of the same which target genes are most likely to
Randy Jirtle
in soy, at doses comparable to those a colleagues also demonstrated that giving mediate adverse effects of the environ-
human might receive from a high-soy diet. the amino acid L-methionine to older ment on diseases, says Melanie Ehrlich, a
genetics may play in human disease, invest- likely continue. prit.” – Ken Garber
ment in this area of study remains tiny
compared to that devoted to traditional
genetics work. Several efforts to change Cancer Research. Reporting on a June 2005 In the United States, the National
that are under way. workshop convened by the American Cancer Institute and the National Human
In Europe, the Human Epigenome Association for Cancer Research, they con- Genome Research Institute formally kicked
Project was officially launched in 2003 by cluded that, despite all the looming diffi- off a major effort 13 December 2005 that
the Wellcome Trust Sanger Institute, culties, such a project is essential, and the will include epigenomic work. The pilot
Epigenomics AG, and the Centre National technology is sufficiently advanced to project of The Cancer Genome Atlas, fund-
de Génotypage. The group’s focus is on begin. ed by $50 million each from the two insti-
DNA methylation research tied to chro- “I think it’s going to happen a lot soon- tutes, is designed to lay the groundwork for
mosomes 6, 13, 20, and 22. They may be er than I thought just a year or so ago,” Jirtle comprehensive study of genomic factors
joined soon by organizations in Germany says. A group of researchers has already start- related to human cancer. The initial three-
and India, where scientists plan to work on ed the footwork to launch a U.S. comple- year effort is expected to focus on just two
chromosomes 21 and X, respectively, says ment to the European Human Epigenome or three of the more than 200 cancers
Sanger senior investigator Stephan Beck. Project effort [see box, p. A165]. known to exist, but if it’s successful in
But comprehensively studying all the Other efforts are gaining ground. developing methods and technologies, the
epigenetic and epigenomic factors related Another European group, the Epigenome number of cancers evaluated could then
to a multitude of diseases and health con- Network of Excellence, took off in June expand. If a high number of cancer genes
ditions will take much more work. “A 2004. This information exchange network are eventually scrutinized, the effort would
[comprehensive] Human Epigenome includes members in the public and pri- be the equivalent of thousands of Human
Project is a lot more complicated than a vate sectors spread throughout ten Western Genome Projects.
Human Genome Project,” Jones says. European countries. Their objectives are to To help push the boundaries further, the
“There’s only one genome, [but] an epi- coordinate research, provide mentors, and NIEHS and the National Cancer Institute
genome varies in each and every tissue.” encourage dialogue via their website. And are in the midst of awarding grants totaling
The Human Genome Project was a world- in Asia, a conference held 7–10 November $3.75 million to study a wide range of epi-
wide effort that took more than a decade 2005 in Tokyo, “Genome-Wide Epigen- genetic topics, such as identification of
and billions of dollars to complete. etics 2005,” was dedicated in large part to high-risk populations, dietary influences
Jones and Robert Martienssen ad- facilitating a coordinated epigenomics on cancer, and detailed study of numerous
dressed some of the complexities of a com- research effort in Japan and possibly all of specific mechanisms linking environmental
prehensive, worldwide Human Epigenome Asia, says Ushijima, one of the conference’s agents with epigenetic mechanisms and
Project in the 15 December 2005 issue of organizers. resulting disease. The dozen or so recipi-
ents are expected to launch their projects
by fall 2006.
Resources The NIEHS has also begun to integrate
epigenomics projects into its research port-
folio over the past five to six years. “It’s an
emerging area that’s very important,” says
Professional Organizations and Projects Frederick Tyson, a program administrator
• DNA Methylation Society (international) in the NIEHS Division of Extramural
http://www.dnamethsoc.com/main.htm Research and Training. And epigenetics is
likely to be one of the half dozen or so most
• Epigenome Network of Excellence (Europe) important considerations as NIEHS pro-
http://www.epigenome-noe.net ceeds with its Environmental Genome
Project, according to institute director
• Human Epigenome Project (Europe)
David Schwartz.
http://www.epigenome.org The DNA Methylation Society, a pro-
fessional group, has been growing slowly
but steadily over the past decade, says
Journal founder and current vice president Ehrlich.
Epigenetics As part of its efforts, the society launched a
http://www.landesbioscience.com/journals/epigenetics/ journal, Epigenetics, in January 2006 with
the goal of covering a full spectrum of epi-
genetic considerations—medical, nutri-
DNA Methylation Database tional, psychological, behavioral—in any
organism. Such groups are a valuable rally-
http://www.methdb.de/front.html
ing point for this field, Jirtle says. He him-
self slowly worked his way into epigenetics
Imprinted Gene Databases from an initial cancer focus, and his segue
is typical of many. “If you study epigenet-
• http://igc.otago.ac.nz/home.html ics, you don’t have a home; we come from
• http://www.geneimprint.com/databases/?c=clist all different fields,” he says.
• http://www.mgu.har.mrc.ac.uk/research/imprinting/
Interest in the private sector is also pick-
ing up. For instance, Epigenomics AG, with
offices in Berlin and Seattle, is working on
early detection and diagnosis of cancer and
endometriosis (for which there is limited mechanistic studies, and bioinformatic Kunio Shiota, a professor of cellular
evidence of an epigenetic component), as strategies. They also say there is a need for biochemistry at the University of Tokyo
well as development of products to predict basics such as standardized reagents and a and one of the co-organizers of the
effectiveness of drugs to treat these diseases. consistent supply of antibodies for testing. November 2005 Tokyo conference, says
Founded in 1998, and now with about 150 Preston agrees with many of these ideas, epigenetic advances will rely in part on a
employees, the company is focusing on and says there is also a need to develop a range of processes that are slowly becoming
DNA methylation mechanisms, and is comprehensive tally of all proteins in the familiar to more researchers—massively
working with companies such as Abbott cell and to get better protein modification parallel signature sequencing (MPSS),
Laboratories, Johnson & Johnson, Philip information. He says universities are recog- chromatin immunoprecipitation microar-
Morris, Roche Diagnostics, Pfizer, and nizing the demand for the talents needed to ray analysis (ChIP-chip), DNA adenine
AstraZeneca. CEO Oliver Schacht says the solve epigenomics problems, and are methyltransferase identification (Dam-ID),
surging interest in this field is typified by increasing their efforts to cover these topics protein binding microarrays (PBM), DNA
the difference between the 2004 American in various ways, especially at the graduate immunoprecipitation microarray analysis
Association for Cancer Research confer- school level. (DIP-chip), and more. Someday, he says,
ence, which had half a dozen or so talks or Other groups are doing their part by these terms could become fully as familiar
posters on epigenetics, and the 2005 event, creating tools to further the field. All the as MRI and EKG.
which had about 200. imprinted genes identified so far are tracked The rapidly growing acceptance of epi-
in complementary efforts by Morison’s and genetics, a century after it first surfaced, is
Tool Time Jirtle’s groups and the Mammalian Genetics a huge step forward, in Jirtle’s opinion.
If epigenetic work is to continue breaking Unit of the U.K. Medical Research Coun- “We’ve done virtually nothing so far,” he
new ground, many observers say technolo- cil. The European managers of the DNA says. “I’m biased, but the tip of the iceberg
gy will need to continue advancing. Jones Methylation Database have assembled a is genomics and single-nucleotide poly-
and Martienssen note in their paper that compendium of known DNA methylations morphisms. The bottom of the iceberg is
there must be additional improvements in that, although not comprehensive, still pro- epigenetics.”
high-throughput technologies, analytical vides a useful tool for researchers investigat-
techniques, computational capability, ing the roughly 22,000 human genes. Bob Weinhold